Osteoarthritis (OA) is a common degenerative joint disease that is the leading cause of chronic disability in the United States. OA primarily afflicts those over 50 years of age, but it is distinct from normal aging. The hallmark of the disease is the loss of articular cartilage, a tissue that is essential for normal joint function. The causes of osteoarthritis have not been fully determined, but risk factors include abnormal mechanical loading related to joint injury, joint instability, joint mal-alignment, and obesity. As such, there is immense interest in understanding the effects of mechanical stimuli on articular cartilage. The hypothesis underlying this proposal is that cartilage deformation on weight-bearing is an important stimulant of progressive degenerative change to the articular cartilage. Preliminary data demonstrate that the inhibition of proteoglycan synthesis that is caused by static compression in calf articular cartilage is ameliorated by IL-1 receptor antagonist and by inhibition of caspase activity, supporting the concept that IL-1 receptors and caspase(s) are critical elements in mechanical signaling and down-stream metabolic effects. The beneficial effect of IL-1 receptor antagonist is an exciting finding that begins to define a signaling pathway activated by mechanical stimulus in cartilage. The broad goal of this proposal is to delineate the linkage between static mechanical compression and the down-regulation of extracellular matrix biosynthesis in cartilage. The goal is approached through four Specific Aims. First, studies will evaluate the IL-1 receptor dependency of compression effects on various metabolic parameters in surface and middle-depth bovine cartilage, and in human normal and OA cartilage. Second, studies will identify the specific caspases that are activated in compressed tissue in an attempt to clarify the involvement of caspase(s) in modulating cartilage metabolism. Third, studies will examine the phosphorylation status and levels of selected molecules in the signaling cascade activated by compression, with a focus on IL-1 receptor and caspase dependency. Fourth, studies will examine the role of IL-1 receptor and caspases on the metabolic effects of hyperosmotic and pH-buffered media, which mimic some of the cellular and physiochemical changes that occur with mechanical compression. The research is expected to define the mechanism(s) whereby cartilage deformation activates IL-1 receptor-dependent signaling pathways and modulates cartilage metabolism.